Paul Lechat

Evaluation of 4-aminopyridine and 3,4-diaminopyridine penetrability into cerebrospinal fluid in anesthetized rats

4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP) when injected intracisternally to anesthetized rats induced qualitatively similar central nervous system stimulant and convulsant effects at equimolar concentrations. Overall penetrability into cerebrospinal fluid of 4-AP is significantly higher than that of 3,4-DAP after single i.v. administration as evaluated by a high-performance liquid chromatographic determination. The present results can account for the lower central nervous system toxicity of 3,4-DAP when compared to 4-AP previously described after systemic administration.

Analysis of the action of 4-aminopyridine during repetitive stimulation at the neuromuscular junction

4-Aminopyridine (4-AP) increased the quantal content (m) of end-plate potentials (e.p.p.s) evoked by continual stimulation (0.2--25 Hz) in frog end-plates depressed by Mg2+. The increase in m was due to an increase in the binomial parameter n. This was interpreted to mean that 4-AP increased the number of activated release sites. In junctions blocked by d-tubocurarine, 4-AP first increased and then decreased the amplitude of e.p.p.s. elicited during a train of stimuli of increasing frequency, indicating that 4-AP increased transmitter release more than mobilization.

Comparison of the chronotropic effect and the cyclic AMP accumulation induced by β2-agonists in rat heart cell culture

1 The chronotropic response and the variation in cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) accumulation induced by isoprenaline and six β2‐selective agonists (fenoterol, salmefamol, soterenol, zinterol, salbutamol and formoterol) were analyzed on cultured heart cells of the rat. 2 The compounds elicited an enhancement of the frequency, but the time course of the variation of the beating rate was not identical for all of them. A rapid onset was observed for isoprenaline, zinterol and formoterol while it was slower for fenoterol, salmefamol and salbutamol. 3 In contrast with isoprenaline, the β2‐selective agonists gave concentration‐beating frequency curves which were not sigmoidal. Their effects extended up to a concentration of 5 to 6 orders of magnitude. Nevertheless, the concentration at which the maximal effect occurred and the intrinsic activities of the various compounds agrees better with the responses observed on guinea‐pig atria than with those on trachea. 4 All the β2‐selective agonists increased the accumulation of cyclic AMP in rat heart cells with a maximal effect at 10−5 m or less. The effects of β2‐agonists on cyclic AMP production showed some analogies with those on beating frequency of the heart cells. The increase in cyclic AMP accumulation induced by β2‐agonists also corresponded to their chronotropic effects on guinea‐pig atria. Thus, the correlation coefficient between the inverse of the log of the concentration producing the half maximal cyclic AMP accumulation in cultured heart cells and the pD2 values on guinea‐pig atria was 0.93. 5 It is concluded that, in contrast to what was observed in other models, the β2‐selective agonists induce an increase in the production of cyclic AMP in rat heart cells. Furthermore, the effects of the β2‐agonists on cyclic AMP accumulation and on beating rate in the heart cells may correspond with their β1‐adrenoceptor potencies.

Inhibitory effect of kanamycin on evoked transmitter release. Reversal by 3,4-diaminopyridine.

The effect of kanamycin (Kn) on evoked transmitter release was examined in frog end-plates in vitro. By a presynaptic action, Kn (0.02 to 1 mM) significantly reduced the amount of acetylcholine liberated by nerve stimulation. In addition to its presynaptic effects, Kn (0.96 mM) decreased the size of the miniature end-plate potentials possibly by acting at the postsynaptic level. 3,4-Diaminopyridine (4.5 microM) reversed the presynaptic effects of Kn but did not modify its postsynaptic action.

Interaction between parathyroid hormone and the β-adrenoceptor system in cultured rat myocardial cells

Abstract The effect of parathyroid hormone (PTH) alone and in combination with dl-sotalol, dl-propranolol, isoprenaline and calcium chloride has been investigated on cultured rat heart cells beating. PTH induced a dose-dependent positive chronotropic effect which was antagonized by sotalol non-competitively. PTH decreased the positive chronotropic effect of isoprenaline by a non-competitive antagonism. PTH reduced the negative chronotropic effect of propranolol by a competitive antagonism and the positive chronotropic effect of calcium chloride by a non-competitive antagonism. Such interactions suggest that PTH may act in vivo not entirely by stimulating a proper receptor.

Energy metabolism of cardiac cell cultures during oxygen deprivation: effects of creatine and arachidonic acid

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Depressed isoprenaline vascular response in endotoxic rats

The injection of a sublethal dose of E. coli endotoxin (0127 B8) to intact rats (2 mg/kg i.v) or adrenalectomized rats (0.01 mg/kg i.v.) depressed hypotensive responses to isoprenaline (0.2, 0.4, 0.8 microgram/kg i.v.) for at least 4 h following endotoxin injection. These findings evidence an early (under 1 h after administration) and long-lasting (over 4 h) depression of the vascular response to isoprenaline in endotoxic rats. This depression was not related to catecholamine adrenal discharge or to the hypotensive and lethal effects of endotoxin.

Prostaglandin synthesis and membrane fatty acid composition in the heart of obese Zucker rats.

Genetically obese Zucker rats share several abnormalities with obese patients: inheritance of the obesity, hyperinsulinemia, hypertriglyceridemia. Because alterations in membrane fatty acid composition and in prostaglandin synthesis can be involved in the genesis of the cardiovascular complications of obesity, cardiac prostaglandins and phospholipid fatty acid composition were compared in obese and lean animals. Obese cardiac tissues produced smaller amounts of prostacyclin, thromboxane A2 and PGE2 than lean (p less than 0.01). The cyclooxygenase pathway and the activation of phospholipase by the calcium ionophore A 23187 were not altered. Phospholipid fatty acid composition of obese tissues was abnormal: the amount of stearic, arachidonic, docosapentaenoic and cervonic acids was decreased, whereas the amount of linoleic acid, the precursor of arachidonic acid, was doubled. It is concluded that obesity in Zucker rats is associated with alteration of cardiac arachidonic acid metabolism and that the alterations associated with obesity can be studied in this rat strain.

Calcium antagonists stimulate prostaglandin synthesis by cultured rat cardiac myocytes and prevent the effects of hypoxia

The effect of three calcium antagonists on the synthesis of prostacyclin (PGI2, assayed as 6-Keto-PGF1 alpha) and PGE2 by cultured rat cardiac myocytes and fibroblasts was investigated. In myocytes only, bepridil, diltiazem and verapamil (10(-9) to 10(-7) M) stimulated PGs synthesis by two- to three-fold, dose-dependently. At a concentration of 10(-6) or 10(-5) M the intensity of the stimulation of PGI2 and PGE2 decreased. Cobalt chloride (2 X 10(-3) M) did not change PGs synthesis (pg/mg of protein/30 min; means +/- SE, N = 10; PGE2: 365 +/- 59 and 463 +/- 89 treated vs controls; PGI2: 824 +/- 214 and 799 +/- 143 treated vs controls). After 30 min exposure of myocytes to hypoxic conditions (glucose-free medium and low PO2), the glycogen content was half that of the controls (P less than 0.001), ATP content did not change and PGI2 and PGE2 synthesis increased (X1.5, P less than 0.05). When applied to myocytes 30 min before inducing hypoxia, the three calcium antagonists stimulated PGs synthesis by three- to seven-fold at maximal effect, and bepridil (10(-8) M) or diltiazem (10(-7) M) prevented the hypoxia-induced decrease in glycogen content. With 10(-5) M drug concentration, the effect on PGs was not significant, except for the effect of bepridil on PGI2 (P less than 0.05). It is concluded that therapeutic concentrations of calcium antagonists simultaneously prevent the decrease in myocyte glycogen induced by hypoxia and stimulate PGs synthesis by myocytes.

BRAIN CONCENTRATIONS OF BIOGENIC AMINES AND THEIR METABOLITES IN TWO TYPES OF PYROGEN‐INDUCED FEVER IN RABBITS

The effects of two bacterial pyrogens (gonococcus vaccine and E. coli lipopolysaccharide) on brain and CSF concentrations of the biogenic amines and their major metabolites were compared in rabbits. Both pyrogens induced a similar fever, but only the lipopolysaccharide elicited marked biochemical alterations. The main changes observed were: a decrease in the concentrations of acid metabolites of dopamine during the upward course of the first peak of fever; a decrease in the hypothalamic concentrations of noradrenaline at the second peak of fever; a general increase in the metabolites of biogenic amines around the second peak and during the fall of fever. The results led to the conclusion that no significant correlation exists between body temperature and brain amine levels in rabbits. The alterations observed could be a consequence of the fever itself when considered in terms of trauma to the organism.